Immunotherapeutic strategies to boost natural immunity against HIV-1 in those who are infected have largely been disappointing, with a few exceptions. Recently, however, the power of the natural immune response has been shown in human and nonhuman primate models. The Visconti patients in France received early antiretroviral drug therapy and then stopped taking their drugs. Their own immune systems appeared to suppress viral replication below detection. In a vaccine model of SIV infection, generation of powerful immunity through a rhCMV-vector approach led to animals with undetectable viral loads after infection. However, viral variation and immune escape is still a major impediment to vaccine induced or natural immunity, and major efforts have been made to determine which immunogens might lead to conserved immunity. As the field moves towards the dream of elimination of HIV from infected persons, combination approaches appear to be needed. More intensive HAART therapy, strategies to flush virus out of the latent reservoir, boosting of immune responses are all important in the goal of a functional cure. Over the past two years, excitement has built with the first patients apparently cured of their HIV infection. n our current grant, a resubmission of a competitive renewal of an R01 grant, we have developed a novel paradigm. Human endogenous retroviruses (HERVs) HERVs are fixed in our DNA, and represent conserved, immutable targets (in contrast to the highly diverse and rapidly changing antigens produced by HIV) for cellular lysis when reactivated in the context of HIV-1 infection. We recently showed that HERV-K-specific CD8+ T cell clones can eliminate cells infected with diverse HIV-1, HIV-2 and SIV strains. This indicates that reactivated HERVs may serve as conserved, host-encoded targets on HIV-1-infected cells, leading to their cytotoxic lysis, and that they can potentially be exploited in a therapeutic vaccine strategy. This grant proposes 3 specific aims. In the 1st specific aim we will identify which HERV sequences are expressed in HIV-1 infection. In the 2nd specific aim we will identify HERV specific T cell clones with anti-HIV activity in vitro. In the 3rd specific aim we will test HERV specific T cells for their ability to ontrol or eliminate HIV-1 infection in the humanized mouse model. Our previous grant produced data that showed that HIV-1 infection leads to HERV expression and stimulates a HERV-specific immune response, which could eliminate HIV-1 infection in vitro. This renewal application builds on the previous grant to address which HERVs are expressed after HIV-1 infection, and thus which HERV specific T cells are most likely to be functional. We will test functionality in a humanized mouse model of HIV-1 infection. The work proposed in this grant has a direct route to a future human trial of HERV specific T cells to eliminate HIV-1 infection.